The high incidence of clozapine-induced myocarditis reported in Australia has led local researchers to warn that this adverse drug reaction may be overlooked elsewhere.
Many of the signs and symptoms of pneumonia are similar to those of myocarditis, including fever, cough, dyspnea, tachycardia, and chest pain. Cases of clozapine-induced myocarditis with these symptoms can easily be diagnosed as pneumonia if specialized cardiac studies are not performed (or not performed in a timely manner).
Some experts are concerned that additional monitoring may hinder the use of clozapine, especially since there are still many patients with refractory schizophrenia receiving treatment in the public sector where resources are lacking.
The addition of troponin and CRP testing to routine blood tests up to day 28 of treatment as well as slow titration may allow monitoring and control of myocarditis and other early onset adverse events.
The high incidence of clozapine-induced myocarditis reported in Australia has led local researchers to warn that such adverse drug reactions may be overlooked elsewhere as well. The study was published in the April 11 issue of the Scandinavian Journal of Psychiatry.
Investigators at Monash University in Melbourne speculated that the incidence of myocarditis within 4 weeks of initiation of the atypical antipsychotic was estimated to be about 3 percent, based on two cohorts of cases reported to a central agency.
This is contrary to conventional estimates of a slightly greater than 1% incidence of such adverse reactions locally in Australia and less than 0.1% elsewhere. In a systematic review of relevant clozapine studies and case reports, the researchers also found that the early clinical presentation of patient symptoms was consistent with myocarditis, and that these symptoms were rarely considered to be associated with typical nonspecific clinical presentations.
Principal investigator Dr. Kathlyn Ronaldson, senior researcher in the Department of Epidemiology and Preventive Medicine at Monash University, noted, “The process of collecting data made us realize that myocarditis is too easily overlooked; we found 10 associated fatal cases where the deceased was not identified and determined to have myocarditis until autopsy.”
A warning message
According to Dr. Ronaldson, “This investigation was derived from a case-control study conducted to explore risk factors for clozapine-induced myocarditis. …… takes into account that it is not yet possible to explain why there is such a difference in the incidence of presumed myocarditis in patients intervening with clozapine in Australia versus other regions, and this still needs to be explored in depth.”
The investigators identified and referenced several possible causes for the high incidence of adverse drug reactions in the Australian region mentioned in the literature, including: susceptibility to genetic and/or environmental factors; differences in clozapine use, particularly in relation to patient age and dose titration; and inconsistency with diagnostic accuracy and reporting.
Although population and prescription differences with other studies were not considered sufficient to explain the inconsistency, the investigators felt that the “plausible explanation” often cited was due to the higher level of awareness of the disease in Australia.
The researchers believe that many factors contribute to this, including the guidelines for monitoring myocarditis issued in 1999 and the practice of hospitalization and appropriate monitoring of patients for initial interventions with clonazepam.
According to Ronaldson, “Initial interventional clozapine requires that patients be monitored for myocarditis with troponin and C-reactive protein at baseline and weekly thereafter until day 28 of treatment. …… If myocarditis is suspected, baseline and late ultrasound cardiac tracings are helpful for diagnosis and severity assessment.”
The researchers noted several adverse manifestations of early clozapine therapy that may be considered for myocarditis in the differential diagnosis, including fever and respiratory disease.
Considering the large number of cases reporting that clozapine can cause fever, the investigators said, “Fever precedes evidence of cardiac damage, is a common feature of myocarditis, and has been reported in psychiatric journals worldwide without being considered in relation to myocarditis.”
The researchers noted that an association between clozapine and respiratory disease or pneumonia has been clearly established, yet myocarditis has not been considered.
In the paper, the researchers suggest that “many of the signs and symptoms of pneumonia are similar to those of myocarditis, including: fever, cough, dyspnea, tachycardia and chest pain.”
”Without (or in time for) specific cardiac studies, cases of clozapine-induced myocarditis with the above symptoms could easily be diagnosed as pneumonia rather than cardiac-related disease.”
Reducing clozapine use?
Two reviews of the study both expressed concern that additional monitoring might reduce clozapine use.
Dr. Oliver Freudenrich of the Schizophrenia Clinical and Research Program at Massachusetts General Hospital said, “I am particularly concerned that unrealistic (or unsupported) recommendations may hinder the use of clozapine, especially since there are still many patients with refractory schizophrenia receiving treatment in the public sector where resources are lacking. “
According to Dr. Jose De Leon of the University of Kentucky Mental Health Research Center, “With limited evidence, we would rather push for safety without creating more clozapine fear and encourage clinical trials for clozapine: slow titration of clozapine in all patients with refractory schizophrenia.”
Dr. Freudenreich similarly endorsed slow titration as a way to reduce the risk of myocarditis and other early-onset adverse events.
In addition, despite concerns that this move would discourage the use of clozapine, Dr. Freudenreich recommends several monitoring tools for timely detection of myocarditis, including: evaluation of inflammatory markers (such as CRP levels and erythrocyte sedimentation rate) and evidence of myocardial injury (such as by monitoring troponin or creatine phosphokinase levels) in addition to routine blood tests for at least the first 4 weeks.
In an interview, Dr. Ronaldson said, “Patients with clozapine interventions in some areas receive blood count testing at baseline and subsequently weekly for several months, and adding two more tests (troponin and CRP) on top of that until day 28 of treatment adds little to no patient or health care The burden on the patient or the institution.